The n e w e ng l a n d j o u r na l of m e dic i n e

Original Article

Pulmonary Illness Related to

E-Cigarette Use in Illinois and Wisconsin —
Preliminary Report
Jennifer E. Layden, M.D., Ph.D., Isaac Ghinai, M.B., B.S., Ian Pray, Ph.D.,
Anne Kimball, M.D., Mark Layer, M.D., Mark Tenforde, M.D., Ph.D.,
Livia Navon, M.S., Brooke Hoots, Ph.D., Phillip P. Salvatore, Ph.D.,
Megan Elderbrook, M.P.H., Thomas Haupt, M.S., Jeffrey Kanne, M.D.,
Megan T. Patel, M.P.H., Lori Saathoff‑Huber, M.P.H.,
Brian A. King, Ph.D., M.P.H., Josh G. Schier, M.D.,
Christina A. Mikosz, M.D., M.P.H., and Jonathan Meiman, M.D.​​

A BS T R AC T

BACKGROUND
E-cigarettes are battery-operated devices that heat a liquid and deliver an aerosol- From the Illinois Department of Public
ized product to the user. Pulmonary illnesses related to e-cigarette use have been Health (J.E.L., I.G., L.N., M.T.P., L.S.-H.),
Springfield; the Epidemic Intelligence
reported, but no large series has been described. In July 2019, the Wisconsin De- Service, Center for Surveillance, Epide-
partment of Health Services and the Illinois Department of Public Health received miology, and Laboratory Services (I.G.,
reports of pulmonary disease associated with the use of e-cigarettes (also called I.P., A.K., M.T., P.P.S.), National Center
for Environmental Health (M.L.), the Di-
vaping) and launched a coordinated public health investigation. vision of State and Local Readiness, Cen-
ter for Preparedness and Response
METHODS (L.N.), the Division of Unintentional In-
We defined case patients as persons who reported use of e-cigarette devices and jury Prevention, National Center for Inju-
ry Prevention and Control (B.H., J.G.S.,
related products in the 90 days before symptom onset and had pulmonary infiltrates C.A.M.), and the Office on Smoking and
on imaging and whose illnesses were not attributed to other causes. Medical record Health, National Center for Chronic Dis-
abstraction and case patient interviews were conducted with the use of standard- ease Prevention and Health Promotion
(B.A.K.), Centers for Disease Control and
ized tools. Prevention, and Emory University School
of Medicine (M.L.) — all in Atlanta; the
RESULTS Wisconsin Department of Health Services
There were 53 case patients, 83% of whom were male; the median age of the patients (I.P., M.E., J.M.), the Wisconsin Division
was 19 years. The majority of patients presented with respiratory symptoms (98%), of Public Health, Bureau of Communica-
ble Disease (T.H.), and the Department
gastrointestinal symptoms (81%), and constitutional symptoms (100%). All case pa- of Radiology, University of Wisconsin
tients had bilateral infiltrates on chest imaging (which was part of the case definition). School of Medicine and Public Health
A total of 94% of the patients were hospitalized, 32% underwent intubation and (J.K.) — all in Madison. Address reprint
requests to Dr. Layden at the Illinois De-
mechanical ventilation, and one death was reported. A total of 84% of the patients partment of Public Health, 69 W. Wash-
reported having used tetrahydrocannabinol products in e-cigarette devices, although ington St., Chicago, IL 60602, or at
a wide variety of products and devices was reported. Syndromic surveillance data ­jennifer​.­layden@​­illinois​.­gov.

from Illinois showed that the mean monthly rate of visits related to severe respiratory This article was published on September 6,
illness in June through August of 2019 was twice the rate that was observed in the 2019, at NEJM.org.

same months in 2018. DOI: 10.1056/NEJMoa1911614

Copyright © 2019 Massachusetts Medical Society.
CONCLUSIONS
Case patients presented with similar clinical characteristics. Although the features of
e-cigarette use that were responsible for injury have not been identified, this cluster
of illnesses represents an emerging clinical syndrome or syndromes. Additional work
is needed to characterize the pathophysiology and to identify the definitive causes.

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 The n e w e ng l a n d j o u r na l
E
lectronic cigarettes, or e-ciga-
rettes, include a diverse group of battery-
powered devices that allow users to inhale
aerosolized substances.1 E-cigarette aerosol gen-
erally contains fewer toxic chemicals than con-
ventional cigarette smoke.2 However, e-cigarette
aerosol is not harmless; it can expose users to
substances known to have adverse health effects,
including ultra-fine particles, heavy metals, vola-
tile organic compounds, and other harmful ingre-
dients.2,3 E-cigarettes are commonly used to inhale
nicotine but can also be used to deliver substanc-
es such as tetrahydrocannabinol (THC), cannabi-
diol (CBD), and butane hash oils (also known as
dabs).4 E-cigarettes entered the U.S. marketplace
Table 1. Outbreak Surveillance Case Definitions of Severe Pulmonary Disease
Associated with E-Cigarette Use — August 30, 2019.*
Confirmed case
Use of an e-cigarette (vaping) or dabbing in 90 days before symptom onset;
and
Pulmonary infiltrate, such as opacities on plain-film radiograph of the chest
or ground-glass opacities on chest CT; and
Absence of pulmonary infection on initial workup: the minimum criteria in-
clude negative respiratory viral panel and influenza PCR or rapid test if local
epidemiology supports testing. All other clinically indicated testing for respi-
ratory infectious disease (e.g., urine antigen testing for Streptococcus pneu-
moniae and legionella, sputum culture if productive cough, bronchoalveolar-
lavage culture if done, blood culture, and presence of HIV-related opportu-
nistic respiratory infections if appropriate) must be negative; and
No evidence in medical record of alternative plausible diagnoses (e.g., cardiac,
rheumatologic, or neoplastic process)
Probable case
Using an e-cigarette (vaping) or dabbing in 90 days before symptom onset;
and
Pulmonary infiltrate, such as opacities on plain film chest radiograph or
ground-glass opacities on chest CT; and
Infection identified by means of culture or PCR, but the clinical team caring
for the patient believes that this is not the sole cause of the underlying respi-
ratory disease process; or as the minimum criteria, to rule out pulmonary in-
fection not met (testing not performed) and clinical team caring for the pa-
tient believes that this is not the sole cause of the underlying respiratory dis-
ease process; and
No evidence in medical record of alternative plausible diagnoses (e.g., cardiac,
rheumatologic, or neoplastic process)
* These surveillance case definitions are from the Centers for Disease Control
and Prevention and are meant for surveillance purposes and not for clinical
diagnosis. They are subject to change and will be updated as additional infor-
mation becomes available, if needed. Vaping was defined as the use of an
electronic device (e.g., electronic nicotine-delivery system, electronic cigarette,
e-cigarette, vaporizer, vapes, vape pen, dab pen, or other device) or dabbing
(superheating in the device for inhaling substances such as nicotine, marijua-
na, tetrahydrocannabinol [THC], THC concentrates, cannabidiol [CBD], syn-
thetic cannabinoids, and flavorings). HIV denotes human immunodeficiency
virus, and PCR polymerase chain reaction.
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of m e dic i n e
around 2007 and since 2014 have been the most
commonly used tobacco product among youths
in the United States.1 During the 2017–2018 period,
the prevalence of current use of e-cigarettes (also
called vaping) increased from 11.7% to 20.8%
among U.S. high school students.5 In contrast,
3.2% of U.S. adults reported current e-cigarette
use in 2018.6
Published case reports have detailed a range
of severe pulmonary illnesses among persons
who have reported use of nicotine or cannabis
extracts in e-cigarettes.7-13 No previous case se-
ries, however, has described large clusters of
temporally related pulmonary illnesses linked to
the use of e-cigarette products (e.g., devices,
liquids, refillable pods, and cartridges).
During July 2019, the Wisconsin Department
of Health Services (WDHS) and the Illinois De-
partment of Public Health (IDPH) received mul-
tiple reports of pulmonary disease of unclear
cause that was possibly associated with the use of
e-cigarettes and related products, which prompt-
ed a coordinated public health investigation. As
of August 27, 2019, a total of 53 cases meeting
the established case definitions (Table 1) have been
reported by clinicians in Wisconsin (28 cases) and
Illinois (25 cases). Similar cases have been re-
ported in at least 25 states, and the Centers for
Disease Control and Prevention (CDC) is coordi-
nating a public health response in multiple states.
In this article, we summarize the clinical char-
acteristics and use of e-cigarettes and related
products reported among the initial 53 case pa-
tients in Wisconsin and Illinois who were identi-
fied as being part of this pulmonary disease
cluster.
Me thods
Outbreak Identification
On July 10, 2019, the Children’s Hospital of Wis-
consin notified the WDHS of five previously
healthy adolescents who had been admitted dur-
ing the previous 30 days with progressive dys-
pnea, fatigue, and hypoxemia. Two patients un-
derwent intubation and mechanical ventilation.
Computed tomography (CT) of the chest in four
patients revealed bilateral ground-glass opaci-
ties, predominantly in the lower lobes. Extensive
infectious, rheumatologic, and oncologic work-
ups were unrevealing. All patients reported a
history of e-cigarette use in the days or weeks
 Pulmonary Illness Related to E-Cigaret te Use
before symptom onset. This report is part of an
ongoing public health investigation.
On July 25, the WDHS issued an alert to clini-
cians describing the clinical syndrome and re-
quested that similar cases of pulmonary disease
associated with e-cigarette use be reported to
public health authorities. The WDHS was subse-
quently contacted by a physician in Illinois seek-
ing clinical treatment guidance for a patient with
similar clinical presentation and e-cigarette prod-
uct exposure, and the WDHS promptly notified
the IDPH on July 31. A joint WDHS–IDPH public
health investigation was initiated on August 1 to
identify additional case patients and to character-
ize the pulmonary clinical syndrome related to
the use of e-cigarettes and related products. The
CDC was consulted for technical assistance early
in the investigation, and a CDC epidemiologic as-
sistance field team (Epi-Aid) was deployed to the
WDHS and IDPH on August 20, 2019.
Case Definition
An outbreak case definition was initially devel-
oped by the WDHS and IDPH and was further
refined in coordination with the CDC and the
Council for State and Territorial Epidemiologists.
Table 1 provides specific details of the probable
and confirmed case definitions. All cases de-
scribed in this article were classified according
to and met the current working outbreak defini-
tions of confirmed or probable cases that has
been mutually accepted by the CDC and the ju-
risdictions that had been affected earliest in the
outbreak (Table 1).
Epidemiologic Investigation
The WDHS and IDPH released their first health
alert notices on July 25 and August 2, respectively,
to inform clinicians of the initial cases and to
request reporting of possible cases to their local
health departments. Medical records were request-
ed for all patients with reported cases. A standard-
ized medical record abstraction form was devel-
oped in Research Electronic Data Capture software
(REDCap, Vanderbilt University) to systemati-
cally collect demographic data on the case pa-
tients, the signs and symptoms at presentation,
laboratory results, imaging findings, reported
drug exposures, clinical course, treatments, and
medical outcomes. Infectious disease and pul-
monary consultations and discharge notes were
reviewed to determine whether causes other than
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vaping were potentially responsible for the clini-
cal syndrome. Medical charts were reviewed by a
group of clinicians from the investigative teams
(six of the authors) with at least two reviewers for
each chart, and discrepancies between reviewers
were adjudicated by means of consensus. A stan-
dardized interview was administered to case pa-
tients to characterize the use of e-cigarettes and
related products in the 3 months before symp-
tom onset. Information regarding such use came
from clinical documentation and interviews with
patients.
Syndromic Surveillance
To assess whether this cluster represented an
increase in severe respiratory illness, the IDPH
established a baseline rate of severe unexplained
respiratory illness by using a syndromic surveil-
lance definition (in contrast to a working out-
break disease-specific case definition). Syndromic
surveillance monitors near-real-time prediagnos-
tic data sources (largely from emergency depart-
ment [ED] visits) to provide early detection of
potential public health threats by means of vali-
dated algorithms.14 Data from the National Syn-
dromic Surveillance Program15 were searched with
the use of the Electronic Surveillance System for
the Early Notification of Community-Based Epi-
demics (ESSENCE) tool, which includes infor-
mation on vital signs, reported symptoms, ED
discharge destination, and diagnosis.15
All ED visits between January 1, 2018, and
August 15, 2019, among persons 14 to 30 years of
age were searched in order to identify encounters
for severe unexplained respiratory illness (defined
in Table S2 in the Supplementary Appendix, avail-
able with the full text of this article at NEJM.org);
searches were limited to counties in Illinois where
cases had already been identified. The syndromic
definition was designed to capture data on pa-
tients who had presented to EDs in Illinois with
severe respiratory symptoms and initial pulse
oximetry of no more than 96% (or if pulse oxim-
etry was not recorded); who were admitted to the
hospital at which they presented or if the discharge
disposition was not to home; and who had a
discharge diagnosis that was not consistent with
a known cause (e.g., bacterial or viral pneumonia
or a chronic respiratory disease such as asthma).
The formulated query was validated to ensure that
it captured data on ED visits by all patients with
confirmed or probable cases in Illinois.
3
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 2. Demographic Characteristics, Symptoms, Evaluation, and Clinical Course of 53 Case Patients.*

Characteristic Values
Median age (range) — yr 19 (16–53)
Male sex — no./total no. (%) 44/53 (83)
Race or ethnic group — no./total no. (%)†
White 37/45 (82)
Black 4/45 (9)
Hispanic 4/45 (9)
Medical history documented in medical record — no./total no. (%)
Asthma 16/53 (30)
Mood or anxiety disorder 18/53 (34)
E-cigarette use in the previous 90 days — no./total no. (%)‡
Reported nicotine use 25/41 (61)
Reported only nicotine use 7/41 (17)
Reported THC use 33/41 (80)
Reported only THC use 15/41 (37)
Reported nicotine and THC use 18/41 (44)
Reported CBD use 3/41 (7)
Symptoms reported at presentation
Median duration of symptoms before presentation (range) — days 6 (0–61)
Any respiratory symptom — no./total no. (%)§ 52/53 (98)
Shortness of breath 46/53 (87)
Any chest pain 29/53 (55)
Pleuritic chest pain 20/53 (38)
Cough 44/53 (83)
Hemoptysis 6/53 (11)
Any gastrointestinal symptom — no./total no. (%)§ 43/53 (81)
Nausea 37/53 (70)
Vomiting 35/53 (66)
Diarrhea 23/53 (43)
Abdominal pain 23/53 (43)
Any constitutional symptom – no./total no. (%)§ 53/53 (100)
Subjective fever 43/53 (81)
Chills 31/53 (58)
Weight loss 14/53 (26)
Fatigue or malaise 24/53 (45)
Headache — no./total no. (%) 21/53 (40)
Vital signs at presentation
Temperature ≥38°C — no./total no. (%) 15/51 (29)
Heart rate >100 beats/min — no./total no. (%) 34/53 (64)
Respiratory rate >20 breaths/min — no./total no. (%) 22/51 (43)
Oxygen saturation while breathing ambient air — no./total no. (%)
≥95% 16/52 (31)
89–94% 20/52 (38)
≤88% 16/52 (31)

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 Pulmonary Illness Related to E-Cigaret te Use

Table 2. (Continued.)

Characteristic Values
Initial laboratory results
White-cell count >11,000/mm3 — no./total no. (%) 45/52 (87)
White-cell count with >80% neutrophils — no./total no. (%) 34/36 (94)
Erythrocyte sedimentation rate >30 mm/hr — no./total no. (%) 14/15 (93)
Sodium <135 mmol/liter — no./total no. (%) 15/49 (31)
Potassium <3.5 mmol/liter — no./total no. (%) 16/46 (35)
Aspartate aminotransferase, alanine aminotransferase, or both — no./total no. (%)
>35 U/liter¶ 20/40 (50)
>105 U/liter‖ 2/40 (5)
Median procalcitonin (IQR) — μg/liter ** 0.58 (0.35–1.00)
Median creatinine (IQR) — mg/dl†† 0.87 (0.76–0.99)
Initial radiographic findings
Abnormal chest radiograph — no./total no. (%) 48/53 (91)
Abnormal chest CT — no./total no. (%) 48/48 (100)
Bilateral infiltrates identified on chest radiograph or CT — no./total no. (%) 53/53 (100)
Treatment
Antibiotics for lower respiratory tract infection — no./total no. (%)
As outpatient 24/53 (45)
During hospitalization 45/50 (90)
Glucocorticoids — no./total no. (%)
Systemic glucocorticoids, oral or intravenous, during hospitalization 46/50 (92)
Intravenous glucocorticoids 38/46 (83)
Had clinical improvement documented with use of systemic glucocorticoids 30/46 (65)
Clinical course
Hospitalization — no./total no. (%) 50/53 (94)
Outpatient or ED visit before hospitalization — no./total no. (%) 36/50 (72)
Median duration of hospitalization (range) — days 6 (1–25)
Receipt of supplemental oxygen — no./total no. (%) 46/53 (87)
Receipt of noninvasive positive-pressure ventilation — no./total no. (%) 19/53 (36)
Intubation and mechanical ventilation — no./total no. (%) 17/53 (32)
Admission to intensive care unit — no./total no. (%) 31/53 (58)
Death — no./total no. (%) 1/53 (2)

* ED denotes emergency department, and IQR interquartile range.

† Race and ethnic group were reported by the patient. Data on race or ethnic group were missing for 8 patients.
Percentages are shown for patients with data.
‡ Some data were missing because a full exposure history was not obtained from interview. Tetrahydrocannabinol
(THC) refers to marijuana-derived extracts or concentrates that contain THC and were used in e-cigarettes.
Cannabidiol (CBD) refers to other cannabis extracts or concentrates that contain CBD as the primary ingredient and
were used in e-cigarettes.
§ The symptoms included in this section are those listed below.
¶ Four patients had documented testing for aspartate aminotransferase only, and one had testing for alanine amino-
transferase only.
‖ A value of more than 105 U per liter is more than three times the upper limit of the normal range, which is used to
indicate severe aminotransferase abnormality.
** Procalcitonin was measured in 21 patients. Reference ranges differed among the hospitals.
†† To convert the values for creatinine to micromoles per liter, multiply by 88.4.

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 The n e w e ng l a n d j o u r na l
Statistical Analysis
Descriptive analyses were performed for all the
patients with confirmed or probable cases that
were reported in Wisconsin and Illinois. Results
were reported as proportions or median values.
All analyses were conducted with the use of Stata
software, version 16 (StataCorp). Proportions re-
garding e-cigarette use were limited to the 41 pa-
tients who underwent extensive interviews re-
garding vaping. To calculate the rate of visits for
severe unexplained respiratory illness according
to syndromic surveillance, a denominator of all
ED visits for the same time period, age range,
and hospitals was used. The mean monthly rates
of ED visits for severe unexplained respiratory
illness per 10,000 ED visits for June 1 through
August 15, 2018, and for June 1 through August
15, 2019, were compared with a two-sided Stu-
dent’s t-test.
R e sult s
Demographic Characteristics of the Patients
As of August 27, 2019, a total of 35 patients had
cases reported to the WDHS, and 47 to the IDPH.
Of the 82 cases reported, 2 were excluded after
chart review, and 27 cases are pending case clas-
sification because of incomplete medical records
or interviews. A total of 53 case patients met the
definition of a probable case (25 total, with 13
in Wisconsin and 12 in Illinois) or a confirmed
case (28 total, with 15 in Wisconsin and 13 in
Illinois). The dates of symptom onset ranged
from April 21 through August 20, 2019, which is
outside the typical influenza season. As of Au-
gust 27, 2019, comprehensive interviews had been
conducted for 77% of the 53 patients with a con-
firmed or probable case.
The median age of the case patients was 19
years (range, 16 to 53) (Table 2); 32% of the pa-
tients were younger than 18 years of age. The
majority of case patients were male (83%). Most
of the patients had no documented relevant
medical history, with no underlying chronic lung
disease except for asthma (which was noted in
30% of the patients). Patients resided in multiple
urban and rural, noncontiguous counties across
both states.
Clinical Presentations
Case patients presented with a combination of
respiratory, gastrointestinal, and constitutional
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of m e dic i n e
symptoms (Table 2). The median duration of
symptoms before hospital presentation was 6 days,
with a wide range (0 to 61 days) of symptom dura-
tion; 72% of patients presented within 7 days
after symptom onset. A total of 72% of the hos-
pitalized patients had been seen in outpatient
settings (EDs, urgent care clinics, or other out-
patient clinics) before admission for related symp-
toms, and 45% of all the patients who were seen
in the outpatient or ED setting received antibi-
otic agents for presumed respiratory tract infec-
tion, primarily oral azithromycin (in 12 of the 24
patients who received antibiotics on an outpa-
tient basis) or levofloxacin (in 4). All the patients
who received antibiotics on an outpatient basis
had reported progression of respiratory symp-
toms, which had prompted subsequent hospital
admission.
A total of 98% of the patients had respiratory
symptoms at hospital presentation (the 1 patient
who reported no respiratory symptoms had an
oxygen saturation of 91% on hospital admission).
The most common respiratory symptoms were
shortness of breath (87%), cough (83%), and chest
pain (55%). Reported gastrointestinal symptoms
included nausea (70%), vomiting (66%), diarrhea
(43%), and abdominal pain (43%). All patients
had one or more constitutional symptoms, with
the most common being subjective fever (81%).
Upper respiratory symptoms such as rhinorrhea,
sneezing, or congestion were not commonly re-
ported.
Details of the vital signs at presentation and
laboratory findings are shown in Table 2. Ac-
cording to the initial recorded vital signs, 64%
of patients had tachycardia (heart rate range,
55 to 146 beats per minute), and 43% had tachy-
pnea (respiratory rate range, 15 to 48 breaths per
minute). At presentation, 38% of the patients had
oxygen saturation between 89% and 94% while
they were breathing ambient air, and 31% had
oxygen saturation of less than 89% while they
were breathing ambient air. A total of 29% of
the patients had a documented fever (tempera-
ture, ≥38°C) at triage, and 53% had a fever re-
corded at some point in their admission, but
medical records were incomplete and this may
be an underrepresentation of the true proportion
with an objective fever.
A high percentage of patients had leukocyto-
sis (87%), defined as a white-cell count of more
than 11,000 per cubic millimeter, with a median
 Pulmonary Illness Related to E-Cigaret te Use
white-cell count of 15,900 per cubic millimeter
(interquartile range, 12,300 to 18,100). A total of
94% of the patients had a neutrophil predomi-
nance (neutrophil percentage, >80%). Among the
27 patients that had an eosinophil percent listed,
none had a value greater than 2%. The erythro-
cyte sedimentation rate was more than 30 mm
per hour in 93% of the 15 patients in whom it
was checked. The median procalcitonin value
was 0.58 μg per liter (reference ranges differed
among the hospitals). Mildly elevated serum
aminotransferase values were noted in 50% of
patients and were transient. Approximately one
third of the patients had mild hyponatremia,
hypokalemia, or both. Acute renal insufficiency
was observed in 1 patient, which resolved with
intravenous hydration.
Cytopathological Findings
A total of 24 patients underwent bronchoalveolar
lavage; the majority of patients received antibiot-
ics, glucocorticoids, or both before the procedure.
Of the 14 bronchoalveolar-lavage specimens with
reported cell counts, the median values were as
follows: eosinophils 0% (range, 0 to 6), neutro-
phils 65% (range, 10 to 91), lymphocytes 7%
(range, 1 to 40), and macrophages 21% (range,
2 to 68). A total of 7 of the 14 cytology reports
on bronchoalveolar-lavage specimens noted lip-
id-laden macrophages with oil red O stain; the
other 7 reports did not comment on the use of
oil red O stain. Of the 7 samples with noted
lipid-laden macrophages, 2 reports listed moder-
ate lipid-laden macrophages, and the rest were
scant to minimal.
Three patients underwent transbronchial lung
biopsy, and two of these patients also underwent
an open lung biopsy, which was performed dur-
ing clinical workup; two of these patients were
receiving both antibiotics and glucocorticoids at
the time, and one was receiving neither before the
procedure. Pathologists reported a range of find-
ings, including mild and nonspecific inflamma-
tion, acute diffuse alveolar damage and foamy
macrophages, and interstitial and peribronchio-
lar granulomatous pneumonitis. Infectious dis-
ease evaluations for possible viral, bacterial, and
fungal pathogens were negative in nearly all case
patients in whom the testing was performed
(Table S1 in the Supplementary Appendix).
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Imaging Findings
At presentation, 91% of the patients had an
abnormal chest radiograph (Table 2). A total of
48 of the 53 case patients underwent CT, and the
findings were abnormal for 100% of these pa-
tients. Opacities in both lungs were present in
100% of the patients. Ground-glass opacities in
both lungs were characteristically observed on
CT, sometimes with subpleural sparing. Of the
48 patients who underwent CT imaging, 4 cases
of pneumomediastinum, 5 pleural effusions, and
1 case of pneumothorax were present (in 8 pa-
tients). One patient had both a pneumomediasti-
num and a pneumothorax, and one patient had
both a pneumomediastinum and pleural effusion.
Clinical Course
All but 3 patients were hospitalized (50 patients
[94%]), and the median duration of hospital stay
was 6 days (Table 2). Intensive care unit admis-
sion for respiratory failure was common (58% of
all patients; 62% of hospitalized patients), and
32% of all patients underwent intubation and
mechanical ventilation (34% of hospitalized pa-
tients). No patient received a tracheostomy.
A total of 15 case patients had documenta-
tion in clinical notes of having acute respiratory
distress syndrome (ARDS). Of these 15 patients,
the investigative team was able to independently
verify that 9 patients (60%) met the Berlin Crite-
ria for ARDS,16 with an average ratio of partial
pressure of arterial oxygen (Pao2; measured in
millimeters of mercury) to fraction of inspired
oxygen (Fio2) of 189. For the remaining 6 pa-
tients, medical records and documentation were
insufficient to verify the diagnosis independently.
Two patients underwent extracorporeal membrane
oxygenation, and one of these patients died. For
both patients, there was clinical documentation
that the ARDS criteria were met.
Most patients received systemic glucocorti-
coids (intravenous or oral) during admission
(92% of the patients overall; 62% received intra-
venous administration). Documentation by the
clinical team that the respiratory improvement
was due to the use of glucocorticoids was found
in the majority of patient notes (65%). All pa-
tients who began receiving systemic glucocorti-
coids were treated with at least 7 days of gluco-
corticoid therapy.
7
 The n e w e ng l a n d j o u r na l
E-Cigarette Use
All patients had a history of use of e-cigarettes and
related products within the 90 days before symp-
tom onset, and 94% of those with data (32 of 34
patients) regarding the date of last use reported
vaping in the week before symptom onset. Most
patients (29 of 33 patients [88%]) reported at
least daily e-cigarette use. Of the 41 patients
who were extensively interviewed, 61% reported
use of nicotine products, 80% reported use of
THC products, and 7% reported use of CBD
products (Table 2). A total of 37% of the patients
reported using THC products only, whereas 17%
reported using nicotine-containing products only.
A total of 44% of the patients reported using
both nicotine and THC products. Patients re-
ported using 14 distinct brands of THC products
and 13 brands of nicotine products in a wide
range of flavors. The most common THC product
that was reported was marketed under the “Dank
Vape” label (reported by 24 of 41 interviewed pa-
tients [59%]). Patients reported use of a number
of different e-cigarette devices to aerosolize these
products. Of the 41 patients who were extensively
interviewed, 7 reported smoking combustible
cigarettes as well.
Clinical Series of Selected Patents
with Confirmed Cases
Figure 1 shows the clinical course of five pa-
tients who met the confirmed case definition
and who underwent intubation and mechanical
ventilation. Representative of the case series in
general, most of the patients had previous out-
patient visits before admission and ultimately
began receiving systemic glucocorticoids.
Select Clinical Vignette with Radiographs
A 17-year-old male patient with no clinically sig-
nificant medical history presented to a hospital
ED with a 2-day history of shortness of breath,
nonproductive cough, and generalized weakness
as well as a 1-week history of fever before presen-
tation, nausea, vomiting, abdominal pain, and
diarrhea. He sought care with his primary care
provider and at multiple EDs for his gastrointes-
tinal symptoms during the week before his ad-
mission and was treated with intravenous fluids
and given metronidazole, levofloxacin, and an
antiemetic agent. His condition worsened, and
new respiratory symptoms developed, so he pre-
sented again to the ED, where he was found to
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of m e dic i n e
have hypoxemia with an oxygen saturation of
85% while he was breathing ambient air, tachy-
cardia with a heart rate of 112 beats per minute,
and a temperature of 37.9°C. A radiograph of the
chest showed opacities in both lungs that were
suggestive of infection or acute lung injury
(Fig. 2A). His laboratory results showed leuko-
cytosis (white-cell count, 18,000 cells per cubic
millimeter) with a neutrophil predominance
(94%) and no eosinophils (0%), as well as elevat-
ed inflammatory markers with a C-reactive pro-
tein level of 32 mg per deciliter and an erythro-
cyte sedimentation rate of 68 mm per hour.
The patient began receiving amoxicillin and
azithromycin as empirical therapy for communi-
ty-acquired and atypical pneumonia and was
admitted to the hospital while he was receiving
3 liters of oxygen per minute through a nasal
cannula. Within hours, he was transferred to the
pediatric intensive care unit owing to respiratory
deterioration. He was intubated and mechani-
cally ventilated, receiving a high Fio2 and positive
end-expiratory pressure, and met the criteria for
moderate ARDS. A radiograph of the chest that
was obtained approximately 12 hours after pre-
sentation showed rapid worsening of diffuse lung
opacities (Fig. 2B), and a high-resolution CT im-
age of the chest showed diffuse hazy ground-
glass opacities with subpleural sparing, findings
consistent with pneumonitis (Fig. 2C through
2E). On day 2 of hospitalization, the patient un-
derwent bronchoscopy, which showed normal-
appearing bronchi. Cytologic testing of bronchoal-
veolar-lavage specimens showed a neutrophil
predominance (78%) with no eosinophils (0%)
and a moderate number of lipid-laden macro-
phages on oil red O staining. Infectious workup,
including blood cultures, testing for human im-
munodeficiency virus (HIV), urinary histoplasma
and blastomyces antigens, polymerase-chain-reac-
tion (PCR) panel for nasopharyngeal respiratory
virus, PCR panel for enteric pathogens, and
bronchoalveolar-lavage studies including bacte-
rial and fungal cultures and pneumocystis stain,
was negative. He began receiving high-dose in-
travenous glucocorticoids on day 2 of the hospi-
talization, and antibiotics were discontinued on
day 4 because an infectious cause was deemed to
be unlikely. The patient’s clinical condition im-
proved, and he was extubated after receiving
intravenous glucocorticoids for 3 days. The pa-
tient was discharged home on hospital day 6 with
 Pulmonary Illness Related to E-Cigaret te Use

Glucocorticoids administered Extracorporeal membrane oxygenation * Outpatient medical visit

Antibiotics administered Hospital admission Continued after discharge
Mechanical ventilation Course of illness Death

Number of Days
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70
Highest available ventilator data

FiO2, 1.0;
Patient 1 VT, 450 ml; 26 breaths/min;
PEEP, 10 cm H2O; Pao2:Fio2, 176

FiO2, 0.6; VT, 450 ml;

Patient 2 PEEP, 10 cm H2O; Pao2:Fio2, 195;
*
plateau pressure, 24 cm H2O

FiO2, 1.0;
VT, 550 ml (7.7 ml/kg IBW);
Patient 3 24 breaths/min; PEEP, 10 cm H2O;
Pao2:Fio2, 96;
plateau pressure, 24 cm H2O
*

FiO2, 0.7; “On a low tidal

Patient 4 volume protocol”; Pao2:Fio2, 207;
PEEP, 10 cm H2O

*
FiO2, 1.0;
VT, 300 ml (5.0 ml/kg IBW);
Patient 5 14 breaths/min; PEEP, 15 cm H2O;
Pao2:Fio2, 59;
plateau pressure, 30 cm H2O
* * *
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70
Number of Days

Figure 1. Clinical Course and Ventilator Use in Selected Patients with Confirmed Severe Pulmonary Disease Who
Were Admitted to an Intensive Care Unit.
Patients were selected if they had a confirmed case of severe pulmonary disease associated with e-cigarette use,
according to the August 30, 2019, outbreak surveillance case definitions of the Centers for Disease Control and Pre-
vention (CDC); if they had been intubated; and if ventilatory requirements for the case definition were documented.
Patient 5 was admitted to the hospital and discharged and was later readmitted. FIO2 denotes fraction of inspired
oxygen, IBW ideal body weight, PaO2 partial pressure of arterial oxygen (measured in millimeters of mercury), PEEP
positive end-expiratory pressure, and VT tidal volume.

instructions to continue an oral glucocorticoid– was twice the mean monthly rate that occurred
tapering regimen for 6 weeks. between June 1 and August 15, 2018 (7.4 cases
per 10,000 visits vs. 3.8 cases per 10,000 visits),
Syndromic Surveillance in Illinois counties. This difference was signifi-
The mean monthly rate of visits to the ED for se- cant for both male and female patients (P<0.05
vere respiratory illness as identified by syndromic for both comparisons; P<0.001 for the combined
surveillance between June 1 and August 15, 2019, comparison) (Fig. 3).

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

C D

Figure 2. Chest Radiographs and High-Resolution Computed Tomographic Imaging in a 17-Year-Old Male Patient
with Diffuse Lung Disease.
In the initial radiograph of the chest at admission (Panel A), the anterior–posterior image shows hazy opacities that
are predominant in the mid and lower lungs. An anterior–posterior radiograph of the chest that was obtained ap-
proximately 12 hours after presentation (Panel B) shows rapid worsening of diffuse lung opacities with developing
consolidation and air bronchograms. Axial (Panels C and D, showing different segments of the lung in order to visu-
alize the extent of the opacities) and coronal reformatted (Panel E) high-resolution CT images of the chest show
ground-glass opacities in both lungs and dense consolidation in a peribronchial and perilobular distribution, with
relative subpleural sparing — findings consistent with an organizing pneumonia pattern of lung injury.

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 Pulmonary Illness Related to E-Cigaret te Use
Discussion
In this report, we describe an ongoing investiga-
tion of pulmonary disease associated with the
use of e-cigarettes and related products in the
days and weeks before symptom onset in two
states. Available data on trends in syndromic
surveillance suggest that the increase in the pa-
tients presenting with severe pulmonary disease
is relatively recent. Although the definitive cause
of this cluster remains unknown, the severity of
the illness and the recent increase in the inci-
dence of this clinical syndrome indicates that
these cases represent a new or newly recognized
and worrisome cluster of pulmonary disease re-
lated to vaping.
E-cigarette liquids and aerosols have been
shown to contain a variety of chemical constitu-
ents that may have adverse health effects.17 Ma-
jor declared constituents in nicotine-based e-
cigarettes include propylene glycol and glycerin,18
in addition to nicotine. Identified contaminants
include polycyclic aromatic hydrocarbons, nitro-
samines, volatile organic chemicals, and inor-
ganic chemicals such as toxic metals.18,19 Endo-
toxins and flavoring compounds such as diacetyl
and 2,3-pentanedione have also been detected.20,21
The health risks of some constituents remain
poorly characterized, and toxicologic assessment
of these substances is an active area of ongoing
research.18,19 In addition to nicotine, e-cigarette
devices can be used to deliver a variety of other
recreational drugs, including THC-based oils.4,22
Although the cause or causes of the reported
illnesses remain under investigation, products
containing THC are the most commonly reported
e-cigarette product exposure among these case
patients (84%). However, 17% of the patients
reported using only nicotine-based products,
and 44% reported using both THC-based and
nicotine-based products. Information on product
use is based on reports by the patients, and pa-
tients may be reluctant to report illicit drug use.
Less clear is the relevance of e-cigarette device
types that were used, as well as the importance of
practice habits (frequency of use, dosing, etc.),
product delivery methods (e.g., adulteration of
devices), and definitive product content. THC-
based oils and waxes can be widely purchased,
despite the fact that they are illegal in the major-
ity of states, including Illinois and Wisconsin,
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14
ED Visits for Severe Unexplained Respiratory Illness
Female patients, 2018
Female patients, 2019
12 Male patients, 2018
Male patients, 2019
10
per 10,000 Visits
8
6
4
2
0
January February March April May June July August
Month
Figure 3. Emergency Department (ED) Visits for Severe Unexplained
Respiratory Illness among Patients 14 to 30 Years of Age, According to
Sex, in Illinois Counties in 2018 and 2019.
The periods of January through August in 2018 and 2019 were compared.
Outbreak-related cases have been identified since April 2019 and are ongoing.
and the content of these products is largely un-
known and unregulated.23
Pulmonary illnesses that have been linked to
e-cigarette use have been limited to individual case
reports. Nicotine-containing liquids have been as-
sociated with a variety of disease presentations.
Diffuse alveolar hemorrhage and exogenous lipoid
pneumonia have been observed.24,25 Acute inter-
stitial lung disease, including acute eosinophilic
pneumonia, respiratory bronchiolitis-associated
interstitial lung disease, and hypersensitivity
pneumonitis, has also been associated with use
of nicotine-containing liquids.7,8,26 Health effects
from dabbing of cannabis concentrates (i.e., su-
perheating of substances containing high levels
of THC or CBD in the device) are less frequently
reported in the literature. Butane hash oil has
been associated with pneumonitis,12,27 and THC
oil has been associated with organizing pneu-
monia.13
In the case series presented here, the popula-
tion was generally young and healthy, yet acute
severe pulmonary disease developed and resulted
in critical care and respiratory support. Given the
disparate nature of e-cigarette–associated illness-
es that have been reported in the literature, it is
11
 The n e w e ng l a n d j o u r na l
notable that case patients in Wisconsin and Illi-
nois presented with similar clinical findings and
progression of disease, which suggests a similar
pathophysiological mechanism of lung injury.
However, the definitive pathology for these pul-
monary diseases has not been established, and
it is possible that these pulmonary diseases rep-
resent a range of disease processes.
As noted above, many chemical constituents
that have been detected in e-cigarette liquids could
cause acute and subacute effects. These constitu-
ents may also undergo thermal decomposition
(pyrolysis) by the metallic e-cigarette heating coils
to produce new compounds in aerosol with dif-
ferent toxicologic profiles.28,29 The coils may also
release metals such as manganese and zinc into
the aerosol, which can be toxic when inhaled.30
Alone or in combination, these substances could
result in a variety of pulmonary illnesses such as
chemical pneumonitis, acute eosinophilic pneu-
monia, acute and subacute hypersensitivity pneu-
monitis, lipoid pneumonia, metal fume fever, and
polymer fume fever. Acute lung injury and ARDS
could result in severe cases.
Of note, eosinophilia was not widely seen in
peripheral blood nor observed in bronchoalveo-
lar-lavage specimens, and characteristic radio-
graphic findings of exogenous lipoid pneumonia
(e.g., low attenuation consolidations) were not
reported in radiograph reports. Among the cyto-
logic reports on bronchoalveolar-lavage specimens
that included information on specific oil stain-
ing, lipid-laden macrophages were reported as
moderate in two and as only “scant” or “minimal”
in the others; specific mention of oil staining was
not provided in the other cytology reports of
bronchoalveolar-lavage specimens. Interestingly,
opacities in both lungs were noted on either ra-
diograph or CT of the chest in all the patients.
A comprehensive review of imaging by a panel
of expert chest radiologists could help to more
completely characterize and identify unique ra-
diographic findings.
The CDC released a Clinical Health Advisory31
on August 30, 2019, recommending that all pa-
tients who report e-cigarette use within the previ-
ous 90 days be asked about signs and symptoms
of pulmonary illness. Clinicians should consider
the possibility of pulmonary disease associated
with vaping when patients report recent use,
especially when other causes are not identified.
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of m e dic i n e
Alternative causes of respiratory illness may be
more likely than vaping, and therefore clinicians
should also continue to consider and appropri-
ately assess for such possible causes of illness in
patients reporting respiratory and gastrointesti-
nal symptoms and e-cigarette use. Although our
current understanding of the appropriate treat-
ment strategies is insufficient to provide clini-
cal recommendations, patients thus far have had
clinical improvement with systemic glucocorticoid
therapy, and the majority of patients have received
prolonged courses.
This article details the clinical spectrums of
the largest cohort of 53 case patients from two
states. Detailed evaluation of medical records,
chest imaging, laboratory results, and exposure
information among these cases provided an op-
portunity to evaluate, characterize, and compare
their clinical courses. Additional data are need-
ed to define the causative exposures. These data
are preliminary and subject to several limita-
tions. Exposure information was reported by the
patients and may be subject to recall error or
hesitancy to report vaping practices. Given the
emerging nature of this syndrome, this initial
series may capture data on patients with more
severe cases who presented for evaluation and
may not capture data on more mild clinical pre-
sentations that were related to the same exposure
or disease process.32 Medical chart data were not
complete for all patients, especially with regard
to respiratory ventilator variables, which limits a
more detailed description of disease severity. Not
all patients had an exhaustive list of negative
findings on serologic tests for infectious causes,
cultures, or molecular studies.
In summary, we report a case series of severe
pulmonary disease associated with the use of
e-cigarettes and related products among gener-
ally young, healthy persons in Wisconsin and
Illinois who presented between April and August
2019. Cases continue to be reported to both these
health departments and across at least 25 states
nationwide. Detailed interviews with patients to
delineate all e-cigarette exposures, including both
devices and substances used, will help to further
narrow the list of potential agents that may be
responsible for the observed increase in pulmo-
nary disease associated with vaping. The WDHS
and IDPH are also working to obtain e-cigarette
devices and liquids for further testing, and the
 Pulmonary Illness Related to E-Cigaret te Use

Forensic Chemistry Center of the Food and Drug used by youths, young adults, pregnant women,
Administration is pursuing nontargeted analyses and adults who do not currently use tobacco
of submitted product samples. products.33
The findings in this report support several
public health recommendations issued by the Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
CDC.33 Since no single product or substance has We thank the staff of the Wisconsin Department of Health
been associated with the illness, persons should Services and Illinois Department of Public Health and numerous
consider not using e-cigarettes while this inves- local health departments and hospitals who played a critical role
in this investigation and collected the information provided in
tigation is ongoing, especially those purchased this article; members of the investigative team, including Carrie
from sources other than authorized retailers Tomasallo and Barbara Grajewski of the Wisconsin Department
(e.g., e-cigarette products with THC) and those of Health Services; Connie Austin, Judy Kauerauf, and Matt
Charles of the Illinois Department of Public Health; and Michael
modified in a manner not intended by the Gutzeit, Lynn D’Andrea, and Lori Loof of the Children’s Hospital
manufacturer. Adult smokers who are attempt- of Wisconsin, for their recognition of the cluster and assistance
ing to quit should consult with their health care with the public health investigation; Grant T. Baldwin, Debra
Houry, Dana Meaney-Delman, and Ileana Arias of the Centers
provider and use proven treatments. Irrespective for Disease Control and Prevention (CDC); and the CDC 2019
of these findings, e-cigarettes should never be Lung Injury Response team.

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